Recently published literature and our unpublished data suggests that HCV may develop several mechanisms to counter the effects of interferon (IFN) and ribavirin, the only therapy available for hepatitis C. The understanding of the mechanism of viral resistance to IFN and ribavirin is important in order to not only understand the mechanism by which recovery or non-recovery from chronic infection occurs during treatment, but also for future improvement in these therapies and the development of new antiviral therapy. Our group has unique collections of serum and liver biopsy samples from patients who received alpha interferon monotherapy, ribavirin monotherapy, or alpha interferon combined with ribavirin, thus allowing critical examination of the clinical significance of these potential mechanisms of viral resistance. The following specific aims will be pursued. Specific Aim 1: Examine the E2 and HS5a sequences in patients who are virological IFN-responders (including end-of-treatment responders and sustained responders) and non-responders (including patients with virologic breakthrough during therapy). The focus will be on the PKR, eIF2alpha-homology domain (PePHD) of E2 and the interferon- sensitivity-determining region (ISDR) of ns5a. Specific Aim 2: Examine the ns5b sequences in patients who have undergone ribavirin-monotherapy, including ALT responders and non- responders (all of them, nevertheless, are virological non-responders). Specific Aim 3: Examine the E2, ns5a and ns5b sequences of patients who have undergone IFN and ribavirin combination therapy. Virological responders (including the end-of-treatment responders and sustained responders) and non-responders (including patients with virologic breakthrough during therapy).